T3 - IE2 - Cardiology - Kaur - Medicinal Chemistry of Anti-arrhythmic Agents

Quinidine due to its _________ character, it is always used in its water soluble salt form e.g., sulfate, gluconate

- basic

Quinidine due to its basic character, is always used as a _______ ________ _______ form

- water soluble salt (due to amine)

e.g., sulfate, gluconate

Quinidine's metabolites include ____________ derivatives at either the ___________ ______ or at the _______ _________.

- hydroxylated

- quinoline ring

- quinuclidine ring

These metabolites possess only about 1/3 the activity of quinidine

Quinidine's metabolites only possess about ______ of the activity of quinidine

- 1/3

Digoxin-quinidine interaction

quinidine (a P-gp substrate) inhibits the renal tubular secretion of digoxin via the P-gp efflux pump, resulting in increased plasma concentration for digoxin

Quinidine is a ___-_____ substrate, which inhibits the renal tubular secretion of ________ via the P-gp efflux pump, resulting in _________ plasma concentration for digoxin

- P-gp (p-glycoprotein_)

- digoxin

- increased

Procainamide Metabolites include

p-aminobenzoic acid and N-acetylprocainamide

Procainamide's acetylated metabolite, __-_______________ is also ________ as an anti-arrhythmic

- N-acetylprocainamide

- active

Procainamide's acetylated metabolite, N-acetylprocanamide is also active as an...

anti-arrhythmic agent.

The metabolites's formation accounts for up to 1/3 of the administered dose and is catalyzed by the liver enzyme N-acetyltransferase

Class IA Sodium Channel Blockers

Quinidine

Procainamide

Disopyramide

Disopyramide is an ________ drug like procainamide and quinidine

- oral

Disopyramide Metabolites include mainly ___-_________ metabolite

- N-dealkylated (by hepatic CYP3A4)

Disopyramide's metabolite retains approximately half the anti-arrhythmic activity of disopyramide

Disopyramide's metabolite retains approximately ______ the anti arrhythmic activity of disopyramide

- half

Phase I Metabolism

usually a reactive functional group is added.

Makes the molecule more soluble, and easier excreted

Phase II Metabolism

GMAS

Glucuronidation

Methylation

Acetylation

Sulfate conjugation

A charged, polar group is added to make molecule even MORE soluble and easily excreted

Class IB Sodium Channel Blockers

Lidocaine

Mexiletine

Lidocaine has a plasma half-life of _____-________ ______

- 15-30 min

Used IV

Lidocaine has a _______ ______ half-life

- very short

Due to easy to hydrolyze functional groups

Lidocaine Metabolites undergo ___-__________, followed by amidase-catalyzed hydrolysis into N-ethylcine and 2'6-dimethylaniline

- N-deethylation

Therefore, it has a very short half-life and used IV

Mexilitine has a ___-_______ group unlike Lidocaine that is believed to _____ the rate of metabolism

- α-methyl

- slow

Thereby, contribute to oral activity

Mexiletine has a half-life of ___-_____ _______ versus Lidocaine's half-life of ___-______ ________

- 12-16 hours

- 15-30 minutes

Mexilitine unlike Lidocaine can be taken in an ________ formulation due to the α-methyl group that is believed to protect it from deamination

- oral

Class IC Sodium Channel Blockers

Fleicanide

Propafenone

Flecainide is ________, therefore a salt can be made

- basic

Flecainide's oral dose is half metabolized by _______________ in the liver and ______ is excreted unchanged in the urine

- CYP2D6

- 1/3

Propafenone's metabolism involves _______ ________ enzymes. It's rate of metabolism is genetically determined by an individual's ability to metabolize the phenotype compounds as _____ or _____ metabolizers

- CYP2D6

- fast

- slow

In over 90% of patients, ____________ is rapidly and extensively metabolized with an elimination half-life of 2-10 hours

- propafenone

(Fast metabolizers); however, this drug has both fast and slow metabolizers

In slow metabolizers, 10% of the population, propafenone's half-life ranges from ___-_____ hours

- 10-32

This is very long compared to fast metabolizers (2-10 hours)

Propafenone Fast Metabolizers Half-life

2-10 hours

Slow metabolizers have less CYP2D6

Class II Antiarrhythmic Drugs

Propranolol

Sotalol

Propranolol is a ___-______ _______ _______

- non-selective β-adrenergic antagonist

Propranolol has a phenyloxypropanolamine functional group

Propranolol has a _______________ group

- phenyoxypropanolamine

Sotalol is a ___________ ___-________ ________ with a ___________ group

- non-selective β-adrenergic antagonist

- phenylethanolamine

Sotalol is a _________________, whereas propranolol is a phenyloxypropnaolamine

- phenylethanolamine

Class III Potassium Channel Blockers

Amiodarone

Dronedarone

Ibutilide

Dofetilide

Amiodarone Drug Interactions

substrate for CYP3A4, Amiodarone's levels are increased by drugs that INHIBIT this enzyme (e.g., histamine H2 blocker cimetidine

Drugs that induce CYP3A4 decrease amiodarone concentration

Amiodarone is a substrate for liver cytochrome __________ and its levels are INCREASED by drugs that __________ this enzyme

- CYP3A4

- inhibit

e.g.,. histamine H2 blocker cimetidine

Drugs that induce CYP3A4 ____________ amiodarone's concentration when co-administered

- DECREASE

Induction of the enzyme, makes it more efficient. Since Amiodarone is also metabolized by CYP3A4. It is broken down faster and concentrations of amiodarone is lower

Amiodarone also inhibits several cytochrome P450 enzymes and may result in high levels of many drugs including...

statins, digoxin, and warfarin

Dronedarone

MULTAQ

CYP3A4 Metabolism

dealkylation

CYP2D6 plays a similar role

Amiodarone has a half-life of ___________, whereas dronedarone has a half-life of _____ _____

- weeks

- 24 hours

In dronedarone, the _______ _____ of amiodraone were removed to reduce toxic effects of amiodarone on the thyroid and other organs

- iodine groups

In dronedarone, the methylsulfonamido group was added to ______ _______ and thus REDUCE neurotoxic effects

- reduce lipophilicity

When compared to amiodarone

After the oral absorption of dronedarone, it is metabolized by the liver enzyme ___________ and undergoes _____-_________ into an active metabolite

- CYP3A4

- N-debutylation

After oral absorption of dronedarone, it ie metabolized by the liver enzyme CYP3A4 N-debutylation into an...

ACTIVE metabolite

Ibutilide used only by ________ ______ as its fumarate salt

- intravenous infusion

Ibutilide Metabolism

High first pass metabolism which results in poor bioavailability when taken orally

Ibutilide has ________ __________ when taken orally

- poor bioavailability

Thus, Ibutilide is used only by intravenous infusion

Ibutilide and Dofetilide have _______________ groups but with _____ ____ ____________ activity

- sulfonamide

- NO β blocking

Dofetilide is used _________

- orally

Dofetilide is well absorbed from the GI tract (bioavailability 96-100%)

Unlike Ibutilide, which is only used IV

Dofetilide is _____ ______ from the GI

- well absorbed (bioavailability 96-100%)

Dofetilide Metabolism

Hepatic CYP3A4 via N-dealkylation and N-oxidation to INACTIVE or MINIMALLY active metabolites

Digoxin is a _______ _______ ______ drug

- glycosidic positive ionotropic

Digoxin is composed of __________ and _______

- polysaccharide (sugar)

- steroid

Digoxin comes from the ________ plant

- foxglove (digitalis)

Steroid portion of digoxin has ____ _________ and ___-___ hydroxyl is conjugated to polysaccharide

- three hydroxyls

- C-3

Digoxin has ______ oral bioavailability, but exhibits inter-individual variability

- good

Each individual is different in terms of bioavailability

Digoxin Half-Life

1.5 - 2.0 days

Digoxin is ________ __-__________ mediated efflux and ___-____ dependent renal elminiation

- intestinal p-glycoprotein

- P-glycoprotein

P-glycoprotein transporters and their substrates, inhibitors, or inducers appear to play an important role in controlling the _______ AUC values through the renal tubular and intestinal secretion.

- digoxin's

This also has an effect on digoxin-drug interactions and digoxin toxicity

Digoxin-Quinidine Interaction: digoxin is actively secreted into he urine by renal tubular cell via the P-gp efflux pump. The digoxin-quinidine interaction is attributed to inhibitor of renal tubular secretion of digoxin by quinidine (a P-gp substrate). Quinidine competitively binds to P-gp in the renal tubule...

reducing the renal section of digoxin by as much as 60% and raising digoxin's plasma concentration to toxic levels

Other drugs that are substrates for renal P-gp are also likely to be associated with digoxin-drug interactions

Concurrent use of cardiac glycoside with ________, ________, ___ _______ _____ and _______ _______ _______, which are substrates for P-gp can alter the control of arrhythmias

- antiarrhythmics

- sympathomimetics

- β adrenergic blockers

- calcium channel blockers

Digoxin-verapamil interaction: associated with ________ digoxin blood levels and ______ with verapamil.

Unlike quinidine, verapamil ____________ _________ ______ _______

- increased

- toxicity

- inhibits intestinal P-gp efflux

Thereby, blocking the intestinal secretion of digoxin into the lumen of the intestine and raising digoxin blood levels to toxic levels

Rifampin-digoxin interaction: rifampin _____________ of ________ _____ _______, thereby increasing the P-gp-mediated secretion of digoxin.

This results in the _______ of digoxin blood levels to _________ concentrations

- induction

- intestinal P-gp expression

- lowering

- subtherapeutic

Digoxin DDI

- digoxin-quinidine (and cardiac glycosides)

- digoxin-verapamil

- Rifampin-digoxin